A randomized phase II trial found that both fluorouracil plus cisplatin and twice-daily radiation and gemcitabine plus once-daily radiation achieved freedom from distant metastasis at 3 years in at least 75% of patients with muscle-invasive bladder cancer.
John J. Coen, MD
A randomized phase II trial found that both fluorouracil plus cisplatin and twice-daily radiation and gemcitabine plus once-daily radiation achieved freedom from distant metastasis at 3 years (DMF3) in at least 75% of patients with muscle-invasive bladder cancer.1
Both regimens are established treatments for selective bladder-sparing treatment of muscle-invasive bladder cancer, noted the authors, led by John J. Coen, MD, of 21stCentury Oncology in Providence, Rhode Island. “The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%,” they wrote in theJournal of Clinical Oncology. “There were fewer toxicities observed in the gemcitabine arm. Either gemcitabine and once-daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy.”
Between December 2008 and April 2014, the investigators enrolled 66 eligible patients with cT2-4a muscle-invasive bladder cancer at 10 US and Canadian centers and randomized them 1:1 to receive either the fluorouracil or gemcitabine regimens. The rate of DMF3 was the study’s primary endpoint, chosen because “distant metastasis is the primary mode of failure for patients with bladder cancer and generally precedes a bladder cancerrelated death.”
Secondary endpoints examined toxicity and efficacy, including complete response (CR) and bladder-intact distant metastasis free survival at 3 years (BI-DMFS3). Treatment was not blinded.
All patients underwent transurethral resection and induction chemoradiation therapy (CRT) to 40 Gy. Chemotherapy doses were fluorouracil 400 mg/m2 on days 1 to 3 and 15 to 17 and cisplatin 15 mg/m2 on days 1 to 3, 8 to 10, and 15 to 17 during induction therapy.
Patients who achieved a CR then received consolidation CRT to 64 Gy. Patients who did not achieve a CR underwent cystectomy. Consolidation chemotherapy consisted of fluorouracil 400 mg/m2 on days 1 to 3 and 8 to 10 and cisplatin 15 mg/m2 on days 1, 2,
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Coen et al. also gave adjuvant chemotherapy: gemcitabine 1,000 mg/m2 on days 1 and 8 and cisplatin 70mg/m2 on day 8, repeated every 21 days for 4 cycles. Paclitaxel 150 mg/m2 was substituted for cisplatin as needed. Patients began adjuvant chemotherapy at either 8 weeks following surgery or 12 weeks following completion of the consolidation regimen.
In assessing the primary endpoint of DMF3, the investigators were able to evaluate 27 patients (82%) in the fluorouracil arm and 25 patients (76%) in the gemcitabine arm. Five patients died before reaching 3 years without distant metastasis.
In the fluorouracil arm, 78% of patients achieved DMF3 (n = 21; 95% CI, 65%-91%). The DMF3 rate in the gemcitabine arm was 84% (n = 21; 95% CI, 72%-96%). The authors noted that this difference was not significant on post-hoc analysis by Fisher’s exact test (P= 0.73) and that both arms met the trial design’s 75% threshold.
Nearly all eligible patients were able to complete induction therapy, with 32 patients (97%) in the fluorouracil arm and 31 patients (94%) in the gemcitabine arm doing so. In the fluorouracil arm, 27 complete responders (93%) finished consolidation therapy and 18 patients (56%) completed adjuvant chemotherapy.
In the gemcitabine arm, 23 complete responders (92%) finished consolidation therapy, and 17 patients (55%) completed adjuvant chemotherapy. Among incomplete responders, 3 of 4 patients in the fluorouracil arm received cystectomy promptly, as did 5 of 7 patients in the gemcitabine arm.
Nearly two-thirds of fluorouracil-arm patients developed treatment-related grade 3 and 4 toxicities during protocol treatment (n = 21, 64%). Hematologic toxicities were most common (n = 18, 55%), followed by GI and genitourinary toxicities with 2 patients (6%).
During the induction regimen, 6 of 33 evaluable patients in the fluorouracil arm (18%) developed treatment-related grade 3 and 4 toxicities. For the consolidation regimen, that rate increased slightly to 21% (6 of 29 patients), followed by a large increase during adjuvant chemotherapy (67%, 18 of 27 patients). One patient in this arm died of an intracranial hemorrhage that the investigators said was likely related to protocol treatment.
Slightly more than half the patients in the gemcitabine arm developed treatment-related grade 3 and 4 toxicities during protocol treatment (n = 18, 55%). Hematologic toxicities were most common (n = 14, 42%), while 3 patients (9%) experienced GI toxicities and 2 patients (6%) had genitourinary toxicities.
One-third of the gemcitabine patients developed treatment-related grade 3 and 4 toxicities during induction chemoradiation (n = 11, 33%). During the consolidation phase, this rate decreased slightly to 29% (7 of 24 patients), followed by an increase to 59% during adjuvant chemotherapy (13 of 22 patients).
According to the authors, there was no significant difference in the occurrence of treatment-related grade 3 or greater toxicity during protocol treatment between arms, with an odds ratio of 0.68 in favor of the gemcitabine arm (P= 0.45). There was also no significant difference in the first occurrence of treatment-related grade 3 or greater toxicity after the end of treatment, with a hazard ratio of 0.81 in favor of the gemcitabine arm (P= 0.64), they wrote.
The median follow-up was 5.1 years (range, 0.4-7.8 years) for eligible living patients, and BI-DMFS3 was 67% for the fluorouracil arm and 72% for the gemcitabine arm. Post-induction CR rates were 88% and 78%, respectively.
Coen JJ, Zhang P, Saylor PJ, et al. Bladder Preservation with Twice-a-Day Radiation Plus Fluorouracil/Cisplatin or Once Daily Radiation Plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712A Randomized Phase II Trial [published online on November 15, 2018].J Clin Oncol.DOI: https://doi.org/10.1200/JCO.18.00537?rel=0" .